The Past, Present, and Future of Hematopoietic Stem Cell Transplantation: Bringing a Radical Cure to Blood Cancers

2020/10/02

Blood cancers, including leukemia, once considered incurable, can now be completely cured thanks to hematopoietic stem cell transplantation (bone marrow transplant). Professor Emeritus Shin-ichiro Okamoto, the first professor of the Department of Hematology at Keio University School of Medicine, which became independent from the Department of Hematology and Rheumatology in 2009, developed a patient-first, team-based medical care system based on the philosophy of the "Four Fs": "For the patient," "For the team," "Fair play," and "Fighting spirit." He laid the foundation for hematopoietic stem cell transplantation in Japan, continued to fight blood cancers by incorporating cutting-edge treatments, and reached retirement age at the end of March 2020. We introduce his passionate approach to the radical cure of blood cancers, based on his final lecture.

"Hematology is simple. You have red blood cells, white blood cells, and platelets, and it's just a matter of whether they increase, decrease, or their quality deteriorates."

During his time as a medical student, Professor Emeritus Okamoto was drawn to the clear and simple hematology taught by the then-Professor Toyama. Fascinated by the world of blood cells unfolding under the microscope, he decided to specialize in hematology. At the time, making diagnoses through morphology was mainstream, and for acute leukemia, CHOP therapy—combining three types of anticancer drugs with corticosteroids—had only just begun. As for chronic myeloid leukemia, a diagnosis meant a "death sentence."

His graduate school research involved the daily routine of observing and analyzing the proliferation of stem cell colonies. However, his research subject was benign diseases, while the actual patients were all suffering from malignant diseases like leukemia. Driven by a desire to be more directly helpful to patients, he and a senior colleague began studying transplantation, and in 1983, they performed their first transplant.

"It was our first time doing everything, and it was chaotic. We believed the patient must not be exposed to outside air, so we sewed sheets together to make a large bag and had the patient get inside it for every radiation therapy session, moving him in a wheelchair. Bone marrow harvesting was also a first for us, and I was incredibly worried about whether we were collecting it properly. The feeling when his white blood cell count started to increase after the transplant was truly special."

One day in 1984, as he was becoming more drawn to the clinical practice of curing patients, a junior physician was diagnosed with chronic myeloid leukemia.

"Someone close to me got leukemia, and I strongly felt that we had to cure him with our own hands. It was then that the direction of becoming a doctor who could cure leukemia became clear to me."

The only treatment that offered hope for a complete cure was hematopoietic stem cell transplantation. He wanted to perform it at Keio University, but unfortunately, the necessary conditions were not yet in place.

"In the end, he departed for the United States to receive treatment. We raised donations among our colleagues, desperately scraped together the travel and treatment costs, and saw him off at the airport by singing "Wakaki-chi"."

If only I could cure those suffering from leukemia... With this strong feeling, Professor Emeritus Okamoto chose the path of mastering hematopoietic stem cell transplantation, a journey he has been on for over 35 years.

Blood cells such as red blood cells, white blood cells, and platelets are differentiated from hematopoietic stem cells located in the bone marrow. Blood cancer occurs when some abnormality arises in these hematopoietic stem cells.

Therefore, hematopoietic stem cell transplantation (bone marrow transplant) is a treatment that aims for a radical cure of the cancer by destroying the abnormal hematopoietic stem cells and transplanting healthy ones.

"As preparation for the transplant (pre-treatment), it is first necessary to eradicate the abnormal hematopoietic stem cells with high-dose chemotherapy or radiation therapy, and at the same time, destroy the patient's immune system. If the immune system is not destroyed, the transplanted hematopoietic stem cells will be recognized as foreign and attacked."

The pre-treatment is extremely powerful and destroys all normal hematopoietic stem cells as well. Healthy hematopoietic stem cells collected from the patient themself or a donor must then be transplanted and engrafted. If successful, blood cells like white blood cells will recover in about two to three weeks, and the immune system will recover in three to four months.

"However, there are still problems. If the hematopoietic stem cells for transplant are collected from a donor, the recipient patient's body is still considered 'foreign' to those cells. This can lead to a troublesome immune disease called 'graft-versus-host disease,' where lymphocytes born from the engrafted donor hematopoietic stem cells attack the patient's normal organs and skin. We also have to deal with organ damage associated with pre-treatment and other factors, as well as viral infections that can occur during the delay in immune reconstitution caused by the use of immunosuppressants. Transplantation is a treatment that can only succeed by steadily controlling these various problems."

At the Fred Hutchinson Cancer Research Center in Seattle, where his junior colleague was hospitalized, world-renowned pioneers of transplant therapy, including Donnall Thomas, were performing the latest transplant therapies. Wanting to learn there, Professor Emeritus Okamoto first studied abroad at Emory University in Atlanta, in the southern United States.

At Emory University, he obtained the ECFMG certification required for clinical training in the US in his first year, and for the next two years, he entered clinical practice and interacted with real patients. Of course, his purpose was to learn about transplant therapy, but he also learned a great deal about the concept of when to withdraw treatment.

"There was an elderly female patient with acute myeloid leukemia whose treatment was difficult, as she did not respond to high-dose cytarabine and other therapies. As I was thinking about what kind of chemotherapy to try next, an experienced physician on site told me, 'Let her die peacefully.' It was the first time I encountered the idea of 'withdrawing' treatment. In Japan at that time, if bad cells appeared, we would thoroughly administer chemotherapy, and I had never seen a peaceful death. In Atlanta, however, the transition to palliative care was remarkably smooth."

At the Fred Hutchinson Cancer Research Center, where he became a long-desired research fellow after his time at Emory University, effective drug therapies to suppress graft-versus-host disease were being developed, and the history of transplant therapy was being rewritten daily.

"Young doctors from around the world received training and then spread new transplant therapies in their respective countries. Transplant therapy had begun its history of expansion."

After gaining experience and honing his skills with cutting-edge transplant therapies, Professor Emeritus Okamoto returned to Japan and launched the first transplant research team at The Institute of Medical Science, The University of Tokyo.

At the Institute of Medical Science, the prevailing approach at the time was aggressive treatment, fighting to the very end. In contrast, based on his experience at Emory University, Professor Emeritus Okamoto believed that withdrawing treatment for the sake of a patient's peaceful death was also an option.

"At first, I think the feeling was, 'Here's a doctor who says something different from everyone else.' There were even heated debates in conferences. However, thanks to the nurses who valued my opinion, I believe a recognition that 'Indeed, that's another way of thinking' emerged among the doctors. The atmosphere of the entire team gradually changed."

From the late 1980s onward, hematopoietic stem cell transplantation saw a series of technological advancements. As a result, transplantation, which was once a last resort, began to be performed in the early stages of disease and was also implemented for benign diseases. Furthermore, in the 1990s, it became possible to collect cells from donors who were not blood relatives as long as their genetic type matched. Cell collection from peripheral blood (in addition to bone marrow) and HLA gene typing, which is involved in distinguishing self from non-self in the immune system, also became possible. This convergence of technological progress led to a dramatic increase in the number of hematopoietic stem cell transplant cases.

Against the backdrop of the increase in transplant therapies, the first bone marrow bank was established in the United States in 1988, and momentum for its establishment grew in Japan as well.

"It was around the time I started working at the Institute of Medical Science. I was entrusted with creating the first system to coordinate patients and donors, and in December 1991, the Japan Marrow Donor Program finally began operations."

Being fluent in English, Professor Emeritus Okamoto ended up handling all international correspondence.

"As soon as word got out that Japan had a marrow bank, a request came from the US to share data, with the expectation that there would be matching marrow for Japanese Americans. But the Japanese bank had just been launched and our system was not yet in place. So, my role was to write letters of apology saying, 'We are very sorry.' In short, I was in charge of handling complaints."

At that time, there was an age limit of 50 for transplantation in Japan, whereas it was 55 in the United States.

"Even when we were asked to provide marrow for patients over 50, it was impossible according to the rules. I kept refusing, but was repeatedly asked, 'Why is it not possible in Japan when it can be done in America?' In the US, it seemed difficult to understand refusing to save a person's life for the reason that 'it's the rule.'"

Eventually, a 55-year-old patient and their doctor came all the way to Japan. Although perplexed, he initially refused as per the rules, but from a humanitarian standpoint, Professor Emeritus Okamoto ultimately gave the go-ahead.

"Then, voices from within rose up, asking, 'Why are you bending the rules?' and it was very tough. But in any case, this became the first case of the Japan Marrow Donor Program providing marrow overseas."

As these steady, individual interactions accumulated, a cooperative system with other countries was built. This system functioned splendidly even during the emergency of the terror attacks in the United States.

"It was when the horrific terror attacks occurred in New York on September 11, 2001. In Japan, there were three patients waiting for marrow donations from America. The phone rang at 3 a.m. A call came from the US, explaining that the situation on the ground was chaotic, making transport difficult, and asking what should be done."

With air traffic control in effect, there was nothing Japan could do but wait.

"But what I found amazing about the American doctors was that they managed to arrange a charter flight and safely delivered the marrow via Hawaii and Guam. The three patients who received transplants at that time are all still doing well today. The system and operational experience of forming a network of patients, donors, marrow bank staff, and medical professionals around the treatment of transplantation became an invaluable asset."

In 1993, Professor Emeritus Okamoto returned to Keio University and launched a transplant team in the Department of Hematology. This new treatment, hematopoietic stem cell transplantation, took firm root in Japan and became the first-line treatment for the chronic phase of chronic myeloid leukemia. By the mid-2000s, the number of patients who had survived for more than 10 years post-transplant was increasing.

"Around this time, the aging of both patients and donors came into focus. In the elderly, cases with various comorbidities are common, regardless of whether they have had a transplant. Furthermore, complications that occur in patients 10 or 20 years after transplantation have also gained attention. Graft-versus-host disease in the elderly is particularly troublesome, and post-transplant mortality rates increase with age.

For donors, the rate of marrow donation also decreases with age, so how to increase and retain young donors has become a challenge."

The idea of taking responsibility for transplanted patients until the very end, even as they become elderly, and the question of what can be done for patients in a world of diversifying values—this awareness of the issues gradually spread.

"When it becomes clear that a patient's condition prevents them from participating in cutting-edge medical care, it does not mean they have been abandoned by medicine. I think the issue is whether we can all recognize and share the value of 'how to live.' Conversely, perhaps this means that everyone needs to cultivate a philosophy of life that allows them to say, 'I will take this path,' when faced with the question, 'Now what?' It's fine to pursue new treatments, and it's also fine to prioritize living joyfully. As for myself, however, it may still be difficult to achieve such a detached perspective."

When the molecular targeted drug imatinib appeared in 2001, it proved effective against chronic myeloid leukemia and came to be used in many cases. However, at present, hematopoietic stem cell transplantation is the only treatment that has shown the potential for a radical cure.

"Since 2010, transplant therapy has entered an era of refinement and harmony. I believe that future transplant therapy will advance toward cell therapies and personalized medicine based on hematopoietic stem cell transplantation."

Currently, new treatments are being developed. These include CAR-T cell therapy, in which a patient's immune cells are collected, genetically modified to incorporate receptors that specifically recognize cancer cells, expanded, and then returned to the patient. Another approach involves creating custom-made vaccines using antigens called neoantigens—which are specifically expressed in each patient due to genetic abnormalities in their cancer cells—to enhance the immune system's ability to attack the patient's cancer cells. It has also become clear that administering high-dose cyclophosphamide, a type of anticancer drug, post-transplant can effectively prevent graft-versus-host disease.

By combining it with these latest treatments, it is becoming possible to further improve the outcomes of hematopoietic stem cell transplantation.

"William Osler, known as the Father of Modern Medicine, said, 'Medicine is science, but medical care is an art based on evidence.' In the future, hematopoietic stem cell transplantation will evolve further as a medical practice, and it will not become obsolete.

I have always felt that medical care, not just transplantation, is similar to a jigsaw puzzle of a masterpiece painting. This is true for any medical practice, but if every single piece of the jigsaw puzzle is not in place and perfectly fitted together, the essential picture will not emerge. What is especially necessary for transplant medicine is not a single master craftsman (master physician), but a team. In a broad sense, this includes everyone, from the patients and donors to the staff of the marrow bank."

The success of the treatment is an honor for every single person involved, and team strength is the great power that supports transplantation. The hematology department's transplant team, which Professor Emeritus Okamoto passionately described and nurtured, was handed over to Dr. Keisuke Kataoka, the new professor, in September 2020. The message Professor Emeritus Okamoto gave to students in his final lecture was: "What can you do for your patients?", "Keep moving forward in the direction you believe is right," and "Even if you reach a dead end, a path will open."

Shin-ichiro Okamoto

Graduated from Keio University School of Medicine in 1979. Received his Ph.D. from the Keio University Graduate School of Medicine in 1983. Studied at Emory University (USA) from 1985, obtained his US medical license in 1986, and engaged in clinical practice from 1987. After serving as a research fellow at the Fred Hutchinson Cancer Research Center in 1989, he returned to the Department of Internal Medicine at Keio University. 1990: Department of Pathological Pharmacology (Division of), The Institute of Medical Science, The University of Tokyo; 1993: Department of Hematology and Rheumatology, Keio University School of Medicine; 2002: Associate Professor at the same department; 2009–2020: Professor, Department of Hematology, Keio University. From 2020, Professor Emeritus of the School of Medicine.